Gene Therapy

Human Gene Therapy
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© Mary Ann Liebert, Inc.

DOI: 10.1089/humc.2018.201
1
The Landscape of Cellular and Gene Therapy Products:
Authorization, Discontinuations and Cost
This paper has been peer‐reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
Vaishali Shukla, MS,1 Enrique Seoane‐Vazquez, PhD, 1 Souhiela Fawaz, PhD, 1 Lawrence
Brown, PharmD, PhD, FAPhA,1 Rosa Rodriguez‐Monguio, PhD.2
1. Chapman University School of Pharmacy,
Harry and Diane Rinker Health Science Campus RK 94‐271,
The Landscape of Cellular and Gene Therapy Products: Cost, Approvals, and Discontinuations (DOI: 10.1089/humc.2018.201)
Downloaded by ALBANY MEDICAL COLLEGE PACKAGE VIA NERL from www.liebertpub.com at 05/26/19. For personal use only.
9401 Jeronimo Road
Irvine, CA 92618‐1908
Phone: 714‐516‐5452
2. Medication Outcomes Center
University of California, San Francisco
533 Parnassus Avenue. U‐12
San Francisco, CA, 94143‐0622
Phone: 415‐502‐6029
Human Gene Therapy
Vaishali Shukla
Research Assistant
Chapman University School of Pharmacy,
Harry and Diane Rinker Health Science Campus
9401 Jeronimo Road
Irvine, CA 92618‐1908
Email: vashukla@chapman.edu
Enrique Seoane, PhD
Professor
Harry and Diane Rinker Health Science Campus RK 94‐271,
9401 Jeronimo Road
Irvine, CA 92618‐1908
Phone: 714‐516‐5452
Email: seoanevazquez@chapman.edu

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Souhiela Fawaz, PhD
Assistant Professor
9401 Jeronimo Road
Irvine, CA 92618‐1908
Phone: 714‐516‐5415
E‐mail: sfawaz@chapman.edu

Lawrence M. Brown, PharmD, PhD, FAPhA
Professor
Chapman University School of Pharmacy
9401 Jeronimo Road
Human Gene Therapy
Irvine, CA 92618‐1908
Phone: 714‐516‐ 5487
Email: seoanevazquez@chapman.edu

Rosa Rodriguez‐Monguio, PhD, MS
Professor, School of Pharmacy
Director, Medication Outcomes Center
University of California, San Francisco
533 Parnassus Avenue. U‐12
San Francisco, CA, 94143‐0622
Office: 415‐502‐6029
E‐mail: rosa.rodriguez‐monguio@ucsf.edu

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Abstract
Background
Cell and gene therapy products belong to a diverse class of biopharmaceuticals known as
advanced therapy medicinal products. Cell and gene therapy products are used for the
treatment and prevention of diseases that until recently were only managed chronically.
The objective of this study was to examine the characteristics of market authorizations,
discontinuations and prices of cellular and gene therapy products worldwide.
Data and Methods
We conducted an electronic search of authorized cell, tissue engineered and gene therapy
products from the databases of the main drug regulatory agencies. The analysis excluded
hematopoietic progenitor cell cord blood products authorized by the US FDA. Price
information was derived from the Red Book (Truven Health Analytics) for the US and from
Human Gene Therapy
health technology assessment agencies, other public sector sources in Europe and
company news. We also searched the scientific literature for authorizations,
discontinuations and price information using MEDLINE/PubMed, Cochrane Library, Google
Scholar, and EMBASE databases. All cost data were converted to US dollars. Descriptive
analysis was conducted in this study.
Results
There were 52 different cell, tissue engineering and gene therapy products with 69 market
authorizations in the world as of December 31, 2018. The products included 18 (34%) cell
therapies, 23 (43.4%) tissue engineered products and 12 (22.6%) gene therapies.
December 31, 2018. There were 21 (30.4% of all authorizations) cell therapy, 26 (37.7%)
tissue engineered and 22 (31.9%) gene therapy market authorizations. The EMA withdrew
the authorization for 2 tissue engineering products, 1 cell therapy and 1 gene therapy, and
New Zealand lapsed approval of 1 cell therapy. Most products were first authorized after
2010, including 10 (83.3%) gene therapies, 13 (72.2%) cell therapies and 13 (56.5%) tissue
engineered products.
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The treatment price for 4 allogenic cell therapies varied from $2,150 in India to $200,000
in Canada. The treatment price for 3 autologous cell therapies ranged from $61,500 in the
UK to a listed price of $169,206 in the US. Tissue engineered treatment prices varied from
$400 in South Korea to $123,154 in Japan. Gene therapy treatment prices ranged from
$5,501 for tonogenchoncel‐L in South Korea to $1,398,321 for alipogene tiparvovec in
Germany.
Conclusions
A significant number of new cell, tissue and gene therapies have been approved in the past
decade. Most products were conditionally authorized and targeted rare cancers, genetic
and other debilitating diseases. However, there are also products approved for cosmetic
reasons. Cell, tissue and gene therapies are among the most expensive therapies available.
Health care systems are not prepared to assume the cost of future therapies for a myriad
of rare diseases and common diseases of epidemic proportions.
Human Gene Therapy
Keywords
cell therapy, autologous, allogenic, regenerative medicine, tissue‐engineered products,
stem cell therapy, gene therapy, ATMP, oncolytic, orphan drug, cost, approval,
authorization, withdrawal, submission, suspended, market discontinuations, EMA, FDA,
PMDA, MFDS, Swiss medic, CFDA, ROSZDRAVNADZOR.

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Introduction
Cell and gene therapy products are biopharmaceuticals used for the treatment of diseases
that until recently were only managed chronically.(1,2) The American Society of Gene & Cell
Therapy defines cell therapy as the administration of living whole cells for the patient for
the treatment of a disease.(3) The origin of the cells can be from an autologous source (i.e.,
same individual) or from an allogeneic source (i.e., another individual). Gene therapy is a
set of strategies that modify the expression of an individual’s genes or repair abnormal
genes. This is achieved by transfer of nucleic acids [deoxyribonucleic acid (DNA) or
ribonucleic acid (RNA)] to somatic cells of a patient which results in a therapeutic effect
that either corrects genetic defects or overexpresses proteins that are therapeutically
useful. (4,5)
Research activities on cell‐based therapy dates back to 1800, but the first successful
hematopoietic stem cell transplantation was accomplished in 1968.(6) There are thousands
Human Gene Therapy
of cell and gene therapy products under development worldwide targeting rare diseases
such as hemophilia, sickle cell disease and Cystic fibrosis, and also global epidemic chronic
conditions such as diabetes, cardiovascular diseases and Alzheimer’s that are potentially
curative (1,7,8).
Regulatory agencies consider cell and gene therapy products as advanced therapy
medicinal products (ATMP). Important differences exist in the regulation, definition, scope,
and approval of gene and cell therapy products by regulatory authorities in the world.(9)
The US FDA and the European Medicines Agency (EMA) explicitly exclude gene‐based
prophylactic vaccines of infectious diseases from their definition of gene therapy; whereas,
the Japanese Pharmaceuticals and Medical Devices Agency (JPMDA) does not.(10) Also,
genetically modified oncolytic viral therapy falls within the definition of gene therapy in
the EU but not in the US. The EMA considers that Hematopoietic progenitor cells cord
blood products do not fit the definition of AMTP because are not subject to substantial
manipulation and are intended to be used for the same essential function in the recipient
and the donor. (11) In addition, talimogene laherparepvec was categorized as a gene
therapy in Europe but not in the US. Therefore, other oncolytic viral therapies may not
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qualify as gene therapy products in the US. Swissmedic classifies cell and tissue‐based
products under transplant products, and specifically excludes cellular therapy intended for
cosmetic use. (12)
The high cost of cell and gene therapy products, coupled with the uncertainty regarding
their safety and effectiveness, present challenges for setting affordable and commercially
viable prices. (13)
Previous studies evaluated cell and gene therapy authorizations with a limited scope (14, 15).
Despite the increase in authorizations and the high cost of gene and cell therapy products,
studies assessing authorizations, discontinuations and prices are lacking. The objective of
this study was to examine authorizations, discontinuations and prices of cell and gene
therapy products worldwide.
Data and Methods
Human Gene Therapy
We conducted an electronic search of authorized cell and gene therapy products from the
databases and webpages of regulatory agencies across the world including Argentina,
Australia, Brazil, Canada, China, EU, India, Korea, Mexico, New Zealand, Philippines, Russia,
Saudi Arabia, South Africa, Sudan, Switzerland, UAE, Ukraine, and US. We also contacted
individuals from regulatory authorities; academia and companies to gather information
that was not readily available.
We also searched the literature using MEDLINE/PubMed, Cochrane Library, Google
Scholar, and EMBASE databases. Search terms used for literature search included
advanced therapy medicinal products, advanced therapies, cell therapy, gene therapy,
regenerative medicine, tissue‐engineered products, stem cell therapy, approval,
submission, suspended, withdraw, and market discontinuations. All searches were
conducted from the inception of the databases until December 31, 2018.
Price information was derived from the Red Book (Truven Health Analytics) in the US, and
from health technology assessment agencies in the EU. We searched for prices in other
countries in public entities, financial news and companies’ web pages.
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We designed a standardized data extraction form using Microsoft Excel to abstract the
following information: authorization date, regulatory review/authorization procedure,
proposed and authorized indication, orphan designation and market status,
manufacturer/company sponsoring the application, discontinuation date, reason for
discontinuation, clinical trial designs, and outcomes used to assess effectiveness.
Hematopoietic progenitor cells cord blood products were excluded from the study.
Descriptive statistics was used for the analysis.
Results
There were 52 different cell, tissue engineering and gene therapy products with 69 market
authorizations in the world as of December 31, 2018 (Tables 1‐3). The different products
included 18 (34.%) cell therapies, 23(43.4%) tissue engineered products and 12 (22.6%)
gene therapies. Autologous cells were the source of 14 (77.8%) different cell therapy
products. Most products were first authorized after 2010, including 10 (83.3%) gene
Human Gene Therapy
therapies, 13 (72.2%) cell therapies and 13 (56.5%) tissue engineered products.
There were 21 (30.4% of all authorizations) cell therapy, 26 (37.7%) tissue engineered and
22 (31.9%) gene therapy market authorizations. The EMA withdrew the authorization for 2
tissue engineering products, 1 cell therapy and 1 gene therapy, and New Zealand lapsed
approval of 1 cell therapy.
Cell Therapy
Between 2001 and 2010, South Korea was the only country that authorized cell therapies
(n=5) (Table 1). By December 31, 2018, South Korea still had the greatest number of cell
therapy authorizations (n=12). Four oncology cell therapy products were conditionally
authorized in South Korea. There were 4 cell therapy products with more than 1
authorization in different regulatory agencies. Remestemcel‐l was approved in Canada
(2012), New Zealand (2012; approval lapsed in 2016 due to lack of use in the country) and
Japan (2015). Sipuleucel‐t was approved in the US (2010) and the EU (2013).
Allogeneic mesenchymal stem cells (Crohn’s disease), allogeneic mesenchymal stem cells
(remediation of hypodermic defective location), autologous BM‐MSC (amyotrophic lateral
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sclerosis), and adipose‐derived stem cells (depressed scar) were granted orphan
designation by the Ministry of food and drug safety‐ South Korea (MFDS). The EMA
granted conditional approval and orphan designation to darvadstrocel (perianal fistulas in
patients with active luminal Crohn’s disease). None of the cell therapy products authorized
in the US were granted orphan designation by the FDA.
Tissue Engineering Therapy
The first tissue engineering product (autologous cultured chondrocytes) was authorized in
South Korea in January 2001 for the treatment of articular cartilage defect of the knee
(Table 2). Between 2001 and 2010, South Korea along with China were the only countries
that authorized tissue engineered products (n=10). Autologous chondrocyte cells was
approved by EMA in 2009 but was later withdrawn from the market. The only Tissue
engineered product granted conditional approval and orphan designation by EMA was
Autologous corneal epithelial stem cells (limbal stem cell deficiency) in 2015. The South
Human Gene Therapy
Korean products autologous cartilage cells and autologous cultured osteoblast were also
authorized in India. By December 31, 2018, South Korea had authorized 34.6% (n=9) of the
world tissue engineered products.
Human autologous skeletal myoblast‐derived cell sheet had a conditional/time‐limited
approval and was granted orphan designation for serious heart failure caused by ischemic
heart disease by the Japanese PMDA. Keratinocyte cells (JACE) was also conditionally
authorized by PMDA.
Gene Therapy
The first gene therapy was a recombinant adenovirus encoding p53 product for treatment
of head and neck cancer authorized in China in 2003 (Table 3). Between 2003 and 2011,
China (n=2), Russia (n=1) and Philippines (n=1) were the only countries with authorized
gene therapies. After 2011, 16 out of the 17 gene therapy authorizations occurred in the
most developed economies. The EU authorized the first gene therapy in 2012 and was the
leader by number of authorizations (n=7) at the end of 2018. The first US gene therapy
approval occurred in 2015 and 3 more products were approved by the US FDA by the end
of 2018. There were 7 (58.3%) gene therapy products authorized for cancer.
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There were 5 (41.7%) gene therapy products authorized by more than 1 regulatory agency.
Tisagenlecleucel was authorized by 5 regulatory agencies (Australia, Canada, Switzerland,
the EU, and the US) for treatment of patients with B‐cell precursor acute lymphoblastic
leukemia and large B‐cell lymphoma.
Within the cohort of regulatory agencies with orphan regulation, 10 (45.5%) gene
therapies were granted orphan designation. Talimogene laherparepvec was granted
orphan designation by the US FDA but not by the EMA and Swissmedic. Tisagenlecleucel
was granted orphan designation by the EMA and the US FDA but not by Swissmedic. (16)
Axicabatagene and voretigene were granted orphan designation by FDA and EMA.
Tonogenchoncel‐L was not granted orphan designation.
Three gene therapy products authorized in the US and 1 in Canada were given priority
review. Axicabtagene ciloleucel was designated as a breakthrough therapy in the US. Both
the FDA and the EMA authorized talimogene laherparepvec following the standard review
Human Gene Therapy
process. Nalotimagene carmaleucel and adenosine deaminase severe combined immune
deficiency therapy were conditionally authorized by the EMA.
Among the authorized gene therapy products around the world, 2 (16.7%) were in vivo
and single dose, 5 (41.7%) were in vivo and multiple doses, 4 (33.3%) were ex vivo and
single dose, and 1 was ex vivo and multiple dose.
The Price of Cell, Tissue Engineering and Gene Therapy
Pharmaceutical companies listed price information was available for 32 (47.05%)
authorizations (Tables 1‐3). The treatment price for 4 allogenic cell therapies varied from
$2,150 in India to $200,000 in Canada. The treatment price for 3 autologous cell therapies
ranged from $61,500 in the UK to a listed price of $169,206 in the US. Tissue engineered
treatment prices varied from $400 in South Korea to $123,154 in Japan.
Treatment price information was available for 16 (72.7%) gene therapy products. Gene
therapy treatment prices ranged from $5,501 for tonogenchoncel‐L in South Korea to
$1,398,321 for alipogene tiparvovec in Germany. Talimogene laherparepvec treatment
price varied from $237,677 for the public sector in Australia to a listed price of $559,293 in
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the US. Tisagenlecleucel treatment prices ranged from $364,948 in the UK to $570,000 in
the US.
Market Discontinuations of Cell and Gene Therapy Products
The EMA withdrew approval of 2 autologous tissue engineered products (autologous
chondrocyte cells (ChondroCelect) and autologous chondrocyte cells (Maci)), 1 autologous
cell therapy (sipuleucel‐t), and 1 gene therapy (alipogene tiparvovec). Two products,
autologous cultured chondrocytes (Maci) and sipuleucel‐t, remained marketed in the US.
Autologous cultured chondrocyte (Maci), a combination of cell and tissue‐engineered
product authorized in 2013, was discontinued from the EU market in September 2014
because the EU registered manufacturing site closed. Likewise, sipuleucel‐t (2013) was
discontinued from the EU market in 2015 following bankruptcy of the sponsor company.
Autologous chondrocyte cells (ChondroCelect) was authorized by EMA in 2009 for the
Human Gene Therapy
repair of single cartilage defect of the femoral condyle of the knee. The product was
discontinued from the market for commercial reasons as several European countries
declined to reimburse the drug due to insufficient evidence on the comparative clinical
effectiveness of the drug.
As of December 31, 2018, alipogene tiparvovec was discontinued in 2017 due to cost and
was the only gene therapy discontinued from the market. (17,18) Alipogene tiparvovec
was authorized for the long‐term correction of lipoprotein lipase deficiency and had a
treatment cost that exceeded $1 million.
New Zealand lapsed the approval of remestemcel‐l (allogenic cell therapy) because it was
not used in the country from approval in 2014 to the middle of 2016.
Discussion
Health care systems around the world are in the early stages of application of cell and
gene therapy in clinical practice. The first cell therapy product was authorized in South
Korea in 2001 and the first gene therapy in China 2003. At the end of 2018, 48 new cell
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and gene therapy products were authorized in the world, most of them in developed
economies.
South Korea led the way in the development and marketing of new cell and tissue
engineering therapies, resulting in 21 new products. However, only a small fraction of
those Korean products was commercialized in other countries where as none of the
Chinese products were commercialized in other countries. South Korea was the first
country to have approved Tissue engineering products. The first authorization of a cell
therapy and a gene therapy in developed economies occurred in Europe in 2009 and 2012,
respectively. At the end of the period of analysis, the EU was the leader, and the US
second, in number of gene therapies products and authorizations. The success of the EU in
the area of gene therapy is explained by the fact that the EU has 28 countries members,
including countries with a highly developed innovator pharmaceutical industry such as
France, Germany and the UK.
Human Gene Therapy
Important differences exist in the regulation of cell and gene therapy in the regulatory
agencies around the world. Previous studies found that differences in drug regulation had
resulted in differences in the characteristics of drugs approved by different regulatory
bodies. (19) Our study found differences in therapy classification, orphan drug designation,
review procedures, and indications of use that could result in differences in clinical
practice in different countries. Differences in definition, scope and regulation of cell and
gene therapy products could be mitigated by improving international regulatory
harmonization efforts.
In the study period, regulatory agencies authorized more products from autologous than
allogenic sources. There is no need for a matched donor for autologous cell therapy
products, lowering the risk of complications and opportunistic infections. Products from
allogenic sources are also considered costlier than products from autologous sources. (20,21)
There were 2 cell therapies (remestemcel‐l and sipuleucel‐t), 3 tissue engineering
(autologous osteoblast cells (Ossron), autologous chondrocytes cells (Maci), and
autologous cartilage cells (Chondron), and 5 gene therapies (axicabtagene ciloleucel,
talimogene laherparepvec, tisagenlecleucel, voretigene neparvovec, and vascular
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endothelial growth factor gene therapy) approved by more than 1 regulatory agency. The
relatively large number of authorizations for gene therapy is related to the need to expand
domestic markets with small number patients and the high cost associated with the clinical
development of gene therapy.
Market discontinuations of cell and gene therapy products were related to commercial
reasons. Cell and gene therapies have very high price (22,23) making challenging for public
and private healthcare systems to provide coverage of those product.(24,25) Alipogene
tiparvovec was withdrawn from the market in 2017 after the Health Technology
Assessment agencies of Germany and France rejected public health insurance coverage of
this therapy indicated for lipoprotein lipase deficiency, an ultra‐rare disease in
Europe.(26,27) And the product was not assessed for public health insurance coverage in any
other European country. Health care systems are not ready for reimbursement of very
high cost treatments that could be required for millions of patients in the immediate
Human Gene Therapy
future.
Cell therapies and gene therapies have garnered significant scientific and public attention
but are moving relatively slowly from bench to authorization for clinical practice. This has
led to the rise of clinics offering unauthorized treatments to critically ill patients seeking
immediate access to potential life‐saving interventions and high‐risk cosmetic
interventions that can cause irreparable harm to patients. (13, 28‐30)
Cell and gene therapies have some of the highest prices of therapies in the health care
system. The combination of high prices and limited evidence about the safety and
effectiveness of cell and gene therapies are important barriers to reimbursement by public
and private payers. Four cell and gene therapies were withdrawn from the EU market after
refusal of coverage by public health care payers.
Our study found large variability of prices around the world, with the US having higher
prices than the rest of the countries. The cost‐effectiveness of cell and gene therapies is
difficult to capture, (16) making it difficult to decide the appropriate reimbursement for
those therapies. Most cell and gene therapies have been approved using conditional
authorization systems that allow for marketing treatment with limited safety and efficacy
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evidence and that may require years to demonstrate their full safety and effectiveness.
(31,32)
Additionally, most gene therapies are orphan drugs for rare diseases and orphan
drugs are typically reimbursed at higher prices than drugs for more common conditions
(33)
. The expansion of the utilization of cell and gene therapies will require difficult decision
of which treatments to cover, particularly when the expected authorization of cell and
gene therapies for common chronic diseases which have a large patient population.
Limitations
Our comprehensive list of authorizations may exclude some products that are not listed in
readily available sources. Some of the product characteristics such as orphan designation
and regulatory review process were not readily available in some countries. Tissue
engineering products originating from xenogenic sources were excluded from analysis.
Some gene, cell and tissue engineering products may be classified by regulatory agencies
under other categories, such as biologics or medical devices.
Human Gene Therapy
There is limited information on the treatment prices of therapy. Available prices exclude
undisclosed rebates and discount that reduce the listed prices and do not necessarily
reflect the actual prices paid to the pharmaceutical companies. We included also the cost
of the product when we calculated the cost of treatment. These advanced products often
require costly health care interventions that may substantially increase the final health
care costs.
Conclusions
A significant number of new cell, tissue and gene therapies have been approved in the past
decade. Most products were conditionally authorized and targeted rare cancers, genetic
and other debilitating diseases. However, there are also products approved for cosmetic
reasons. South Korea and China led the initial authorizations of cell and gene therapies,
respectively, in the world. Authorizations in the EU and the US occurred mostly after 2010,
and by the end of 2018 they become leaders in gene and cell therapy. Cell, tissue and gene
therapies are among the most expensive therapies available. Health care systems are not
prepared to assume the cost of the development of those therapies for a myriad of rare
diseases and more common diseases of epidemic proportions.
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Authors’ Disclosures of Potential Conflicts of Interest
Vaishali Shukla, MS works at uniQure. This manuscript is related to my doctoral studies at
Chapman University. There are no financial conflicts of interest and no relationship to
uniQure related to this study.
Enrique Seoane‐Vazquez, PhD, Souhiela Fawaz, PhD, Lawrence Brown, PharmD, PhD,
FAPhA, and Rosa Rodriguez‐Monguio, PhD have no relationship to disclose.

Human Gene Therapy
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32. Senior M. Rollout of high‐priced cell and gene therapies forces payer rethink. Nat
Biotechnol. 2018;36:291.
33. Seoane‐Vazquez E, Shukla V, Rodriguez‐Monguio R. Innovation and competition in
advanced therapy medicinal products. EMBO Mol Med, 2019.
34. Jayaraman KS. India’s first stem cell‐based drug Hope for patients facing limb
amputation. Nature India [Internet]. 2016. Available from:
Human Gene Therapy
https://www.natureasia.com/en/nindia/article/10.1038/nindia.2016.61
35. National Institute for Health and Care Excellence. Appraisal consultation document
Darvadstrocel for treating complex perianal fistulas in Crohn’s disease. 2018.
36. Busa Consulting LLC. Counting Coup: Is Osiris Losing Faith In Prochymal? [Internet].
2017. Available from:
http://busaconsultingllc.com/scsi/organelles/counting_coup_prochymal.php
37. Sakai D, Schol J, Foldager CB, Sato M, Watanabe M. Regenerative technologies to bed
side: Evolving the regulatory framework. J Orthop Translat. 2017; 9: 1‐7.
38. National Institute for Health and Care Excellence. Cost to NHS of providing sipuleucel‐T
too high to be recommended in draft guidance [Internet]. 2014. Available from:
https://www.nice.org.uk/news/press‐and‐media/sipuleucel‐t‐cost‐too‐high‐for‐nhs‐draft‐
guidance
39. Cheng B, Lu S, Fu X. Regenerative medicine in China: main progress in different fields.
Military Medical Research (2016) 3:24
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40. Apollo Hospitals ties up with Regenerative Medical Services Regrow for cell‐based
therapy. The Hans India [Internet]. June 17, 2017. Available from:
https://www.thehansindia.com/posts/index/Health/2017‐06‐19/Apollo‐Hospitals‐ties‐up‐
with‐Regenerative‐Medical‐Services‐Regrow‐for‐cell‐based‐therapy/307449
41. Bravery CA. Are Biosimilar Cell Therapy Products Possible [Presentation]. Bioprocessing
and Stem Cells Europe 2012. London, UK, June 2012. Available from:
advbiols.com/documents/Bravery‐AreBiosimilarCellTherapiesPossible.pdf
42. Medical Services Advisory Committee. Matrix‐induced autologous chondrocyte
implantation and autologous chondrocyte implantation. Assessment Report.
Commonwealth of Australia, December 2010. Available from:
http://www.msac.gov.au/internet/msac/publishing.nsf/Content/E72BFBEC5447F91FCA25
801000123B6D/$File/1140_Report_Final040211.pdf
Human Gene Therapy
43. Mistry H, Connock M, Pink J, Shyangdan D, Clar C, Royle P, Court R, Biant LC, Metcalfe
A, Waugh N. Autologous chondrocyte implantation in the knee: systematic review and
economic evaluation. Health Technol Assess. 2017;21(6):1‐294.
44. National Institute for Health and Care Excellence. Appraisal consultation document
Holoclar for treating limbal stem cell deficiency after eye burns [Internet]. 2017. Available
from: https://www.nice.org.uk/guidance/ta467/documents/appraisal‐consultation‐
document‐2
45. Aesha D. Repairing painful joints: RMS Regrow to offer cartilage therapy using own
cells. The Hindu‐Business line [Internet]. 2017; Available from:
https://www.thehindubusinessline.com/news/science/repairing‐painful‐joints‐rms‐
regrow‐to‐offer‐cartilage‐therapy‐using‐own‐cells/article9640453.ece
46. Jae‐hyeon S. Will Tego Science win reimbursement for diabetic foot ulcer treatment?
[Internet]. 2018. Available from:
http://www.koreabiomed.com/news/articleView.html?idxno=3971
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20
47. Hildreth C. Pricing Of Approved Cell Therapy Products – Stem Cells, CAR‐T, And More
[Internet]. 2017. Available from: https://bioinformant.com/price‐of‐cell‐therapy‐
products/#_ftn21
48. Federal Joint Committee on an amendment to the Pharmaceutical Directive (AM‐RL).
Resolutions on the benefit assessment of pharmaceuticals with new active ingredients, in
accordance with the German Social Code, Book Five (SGB V), section 35a Alipogene
tiparvovec [Internet]. 2015. Available from: http://www.english.g‐ba.de/downloads/91‐
1028‐146/2015‐05‐21_Alipogene‐tiparvovec_D‐138_EN.pdf?
49. National Institute for Health and Care Excellence. Strimvelis for treating adenosine
deaminase deficiency–severe combined immunodeficiency [Internet]. The Technology.
2018. Available from: https://www.nice.org.uk/guidance/hst7/chapter/3‐The‐technology
50. MolMed S.p.A. AIFA set the reimbursement price for Zalmoxis® at EUR 149.000 per
Human Gene Therapy
infusion, gross of discounts foreseen by law, and also established a flat fee per patient.
Press Release. December 13, 2017. Available from:
https://www.molmed.com/sites/default/files/uploads/press‐
releases/3225/3225_1513170251.pdf
51. MolMed S.p.A. Zalmoxis®: Price & reimbursement dossier filed in Germany, where the
product can be prescribed and reimbursed as of January 15. Press Release. January 16,
2018. Available from: https://www.molmed.com/sites/default/files/uploads/press‐
releases/3231/3231_1516085497.pdf
52. Kudrin A. Business models and opportunities for cancer vaccine developers. Hum
Vaccines Immunother. 2012;8(10):1431–8.
53. Daytona. Rexin‐G [Internet]. Cancer Compass. 2008. Available from:
https://www.cancercompass.com/message‐board/message/all,1192,2.htm?mid=273632
54. Gemeinsame Bundesausschuss. Dossier zur Nutzenbewertung gemäß § 35a SGB V. June
14, 2016. https://www.g‐ba.de/downloads/92‐975‐1519/2016‐06‐
14_Modul3A_Talimogen%20laherparepvec.pdf
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55. Pharmaceutical Benefits Advisory Committee (PBAC). Talimogene laherparepvec Intra‐
lesional injection, 1 million and 100 million PFU/mL Public Summary Document – July 2016
PBAC Meeting. Available from: http://www.pbs.gov.au/industry/listing/elements/pbac‐
meetings/psd/2016‐07/files/talimogene‐psd‐july‐2016.pdf
56. National Institute for Health and Care Excellence. Tisagenlecleucel for treating relapsed
or refractory diffuse large B‐cell lymphoma after 2 or more systemic therapies. Final
appraisal document. Available from: https://www.nice.org.uk/guidance/gid‐
ta10269/documents/final‐appraisal‐determination‐document
57. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen. Tisagenlecleucel
(diffuses großzelliges B‐Zell‐Lymphom) – Bewertung gemäß § 35a Abs. 1 Satz 11 SGB V.
December 13, 2018. Available from: https://www.g‐ba.de/downloads/92‐975‐2575/2018‐
09‐15_Bewertung‐Therapiekosten‐Patientenzahlen‐IQWiG_Tisagenlecleucel‐DLBCL‐D‐
375.pdf
Human Gene Therapy
58. Novartis leukaemia drug approved in Switzerland. Swissinfo.ch. October 22, 2018.
Available from: https://www.swissinfo.ch/eng/sci‐tech/kymriah_novartis‐leukaemia‐drug‐
approved‐in‐switzerland/44490894
59. Jae‐doo Y. What are doctors’ views on Invossa used even by foreign patients?
[Internet]. 2017. Available from:
http://www.koreabiomed.com/news/articleView.html?idxno=2004
60. Isaev A. Gene therapy drug approved on Russian market [Internet]. Cell Trials. 2011.
Available from: http://celltrials.info/2011/12/19/gene‐therapy‐drug‐approved‐russian‐
market‐interview‐artur‐isaev/

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22
Table 1. Authorizations and Prices at Market Entry of Cell Therapy Products
Non‐proprietary name Country/ Approval Date Price at
Indication
eviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
(Product name) Jurisdiction Market

Orphan Entry Source
(US Dollars)
Allogenic Cell Therapy
he Landscape of Cellular and Gene Therapy Products: Cost, Approvals, and Discontinuations (DOI: 10.1089/humc.2018.201)
Allogeneic pooled Critical limb ischemia due to India May 2016 NA $2,150 34

human bone marrow‐ Buerger's disease
derived mesenchymal
stromal cells
(Stempeucel)
Darvadstrocel (Alofisel) Complex perianal fistulas in European 3/23/2018 Yes $70,632 (UK) 35
adult patients with Union
Human Gene Therapy
nonactive/mildly active
luminal Crohn’s disease, when
fistulas have shown an
inadequate response to at
least one conventional or
Page 23 of 47

23
biologic therapy.
Remestemcel‐l Management of acute Graft Canada 5/17/2012 NA $200,000 36

(Prochymal) versus Host Disease in pediatric
patients.
Remestemcel‐l Rescue of patients NLT 6 New Zealandǂ 6/14/2012 NA N/A

(Prochymal) months to 17 years of age
with acute graft versus host
disease, refractory to
treatment with systemic
corticosteroid therapy or
other immunosuppressive
agents. Prochymal use under
Human Gene Therapy
these conditions is limited to
Grades B to D of the disease
Remestemcel‐l (Temcell) Acute Graft versus Host Disease Japan 9/18/2015 Yes $7,248 37
Thermosensitive Deep 2nd degree burns (skin South Korea 10/16/2015 NA N/A

Page 24 of 47

24
hydrogel‐type cultured regeneration)
allogenic epithelial
allograft (Keraheal‐Allo)
Autologous cell therapy
Autologous adipose‐ Depressed scar South Korea 9/14/2007 Yes N/A
derived stem cells
(Adipocell)
Autologous adipose‐ Crohn's disease South Korea 1/18/2012 Yes N/A
derived stem cells
(Cupistem)
Autologous adipose‐ Remediation of hypodermic fat South Korea 3/26/2010 Yes N/A
derived stem cells defective location
(Queencell)
Human Gene Therapy
Page 25 of 47

25
Autologous bone Acute myocardial infarction South 7/1/2011 NA N/A

marrow‐derived Korea
mesenchymal stem cells
(HeartiCellgram‐AMI)
Autologous Immunotherapy for prostate, ovarian, colorectal and
India March NA N/A
dendritic cells non‐small cell lung carcinoma
2017
(Apceden)
Autologous Metastatic renal cell carcinoma South 5/15/2007 NA N/A
dendritic cells Korea
(CreaVax‐RCC)
Autologous Hepatoma South 8/6/2007 NA N/A
dendritic cells Korea
(Immuncell‐LC)
Human Gene Therapy
Autologous dendritic cells non‐small cell lung cancer South 2/14/2007 NA N/A

(Innolak) Korea
Autologous fibroblasts Treatment of nasojugal grooves, or tear trough South 12/27/2017 NA N/A
(Rosmir) deformities Korea
Page 26 of 47

26
Autologous matural Malignant Lymphoma South 8/7/2007 NA N/A
killer mix cells (NKM) Korea
Autologous Remediation of hypodermic fat defective location South 2/1/2010 NA N/A
mesenchymal stem Korea
cells (Autostem)
Amyotrophic lateral sclerosis South 7/30/2014 Yes N/A
Autologous
mesenchymal stem Korea
cells (Neuronata‐R)
Improvement of the appearance of moderate to
Azficel‐t (Laviv) US 6/21/2011 No N/A
severe nasolabial fold wrinkles in adults.
Sipuleucel‐t (Provenge) Treatment of asymptomatic or minimally symptomatic US 4/29/2010 No $169,206 AWP
metastatic castrate resistant (hormone refractory)
prostate cancer.
Human Gene Therapy

Human Gene Therapy

Page 27 of 47

(Provenge)
Sipuleucel‐t
ǂ =Withdrawn/Suspended from the market.
Treatment of asymptomatic or minimally
chemotherapy is not yet clinically indicated.
symptomatic metastatic (non‐ visceral) castrate
resistant prostate cancer in male adults in whom
Unionǂ
European
9/6/2013 No
$61,500 38
27
Page 28 of 47

28
Table 2. Authorizations and Prices at Market Entry of Tissue Engineered Products

AlloDerm
To repair defect of human dermal China 2010 N/A N/A 39
Allogeneic bone grafts Dental implants, to repair broken bones that have
bone loss, and repair broken bone that has not yet China 2011 N/A N/A 39
healed

Allogeneic cultured Topical (non‐submerged) application to a surgically US 3/9/2012 No N/A
keratinocytes and created vascular wound bed in the treatment of
fibroblasts (Gintuit) mucogingival conditions in adults.

Autologous bone
Human Gene Therapy
Local bone formation‐‐local osteoblastic palpation South 8/26/2007 No N/A

marrow derived stem (enhancing reconstruction) Korea
cells (RMS‐Ossron)
Page 29 of 47

29


Autologous Repair of articular cartilage of the joint (knee, ankle,
cartilage cells shoulder) in adults designed to help replace areas of India 4/13/2017 NA $5,740 40
(Cartigrow). cartilage that are missing because of injury, or wear and
Marketed as tear.
Chondron in
South Korea
Autologous cartilage cells Articular cartilage defect (knee) South 1/30/2001 No N/A
(Chondron) Korea

Autologous cartilage cells For traumatic cartilage defect of knee joint Japan 7/27/2012 No N/A
(JACC)
Human Gene Therapy

Repair of single symptomatic cartilage defects of the
Autologous femoral condyle of the knee (International Cartilage European
5/10/2009 No $24,000 41
Human Gene Therapy

Ortho‐ACI)
Autologous
(ChondroCelect)
chondrocyte cells
chondrocyte cells
(Chondrocytes ‐ T ‐

ankle
grade I or II) might be present.
Repair Society [ICRS] grade III or IV) in adults.
Concomitant asymptomatic cartilage lesions (ICRS
Cartilage lesions associated with the knee, patella and

Unionǂ
Australia

5/26/2017

No

(UK)
$11,400

42
30
Page 30 of 47
Page 31 of 47

31
Autologous
chondrocyte cells Diabetic foot ulcer South 9/14/2007 No N/A
(Hyalograft‐3D) Korea
Autologous Repair of symptomatic, full ‐thickness cartilage European

defects of the knee (grade III and IV of the Modified 6/27/2013 No $21,000 43

chondrocyte cells Unionǂ
Outerbridge Scale) of 3‐20 cm2 in skeletally mature (UK)
(Maci)
adult patients.
Autologous Repair of single or multiple symptomatic, full‐ US 12/13/2016 No $28,650 AWP

chondrocyte cells thickness cartilage defects of the knee with or
(Maci) without bone involvement in adults.
Human Gene Therapy
Autologous corneal Treatment of adult patients with moderate to European

2/17/2015 Yes $105,000 44
epithelial stem cells severe limbal stem cell deficiency Union
(UK)
(Holoclar)
Autologous human
Page 32 of 47

32
epidermal
Treatment of burn wounds South 5/3/2006 No N/A

kertinocytes Korea
(KeraHeal)
Autologous human 12/10/2002
epithelial cells Treatment of burn wounds South No N/A
(Holoderm) Korea
Autologous
keratinocyte cell (LSK‐ Skin burn therapy South 9/17/2010 No N/A
Autograft) Korea
In patients with serious, extensive burns when
Autologous
sufficient donor sites for autologous skin grafts are not
Human Gene Therapy
keratinocyte cells Japan 9/29/2016 No N/A

available and the total area of deep dermal and full‐
(JACE)
thickness burns is 30% or more of the total body
surface area.
Autologous osteorblast
cells (Ossgrow). Avascular necrosis of hip joint India April 2017 NA $2,800 45
Page 33 of 47

33
Marketed as Ossron in
South Korea.
Autologous skeletal
myoblast cells For serious heart failure caused by ischemic heart Japan 9/18/2015 No $123,154 37
(HeartSheet) disease
Autologous somatic cell
fibroblasts (Cureskin) Remediation of depressed fibrotic scars location with South 5/11/2010 No N/A

acne Korea
Composite of
allogeneic umbilical Treatment of knee cartilage defects in patients with
South 1/18/2012 No N/A
cord blood‐derived Osteoarthritis (OA) due to degeneration or repetitive
Korea
mesenchymal stem trauma
cells and hyaluronate
Human Gene Therapy
hydrogel (Cartistem)
Cultured allogenic
keratinocytes Burn wounds South 3/21/2005 No $400 46
(Kaloderm) Korea
J‐1 allogeneic To repair oral
Page 34 of 47

34
acellular mucosal defects, soft China 2006 N/A N/A 39

dermal matrix tissue defects
To repair various
Rhino (acellular causes of oral
dermal matrix mucosa and soft
tissue defect. Closing China 2007 N/A N/A 39
medical tissue
patch) the wound, dental
implantation, hernia
repair, urethral
Spheroids of human Repair of symptomatic articular cartilage defects of the European $9,000‐

autologous matrix‐ femoral condyle and the patella of the knee Union 7/12/2017 No $12,000 47
Human Gene Therapy
associated (International Cartilage Repair Society [ICRS] grade III

chondrocytes or IV) with defect sizes up to 10 cm2 in adults.
(Spherox)
Human Gene Therapy

Page 35 of 47
Tissue engineering skin
than 5 cm)
To repair deep II
not more than III
degree burn wound
degree burn wound,
20 cm2 (diameter less
China
2007
N/A
N/A
39
35
Page 36 of 47

36
Table 3. Authorizations and Prices at Market Entry of Gene Therapy Products


Non‐ Country/ Method and Approval
proprietary Indication Jurisdiction Frequency of Date
name (Product administration Price at
name) Market
Orphan Entry (US Source

Dollars)
Gene Therapy

Adult patients
diagnosed with European In vivo, single $1,398,321
Human Gene Therapy
Alipogene tiparvovec familial lipoprotein Unionǂ dose 10/25/2012 Yes (Germany) 48

(Glybera) lipase deficiency and
suffering from severe
or multiple
pancreatitis attacks
despite dietary fat
Page 37 of 47

37
restrictions.

Autologous CD34+

enriched cell
Treatment of severe
fraction that
combined European Ex vivo, single
contains CD34+ 5/26/2016 Yes $690,000 49
immunodeficiency Union dose
cells transduced
due to adenosine
with retroviral
deaminase deficiency,
vector that
encodes for the for whom no suitable
human leukocyte
human adenosine
antigen‐matched
deaminase cDNA
Human Gene Therapy
related stem cell
sequence from
donor is available.
human
haematopoietic
stem/progenitor
cells (Strimvelis)
Page 38 of 47

38


Treatment of adult
patients with relapsed Ex vivo, single
axicabtagene or refractory large B‐ US dose 10/18/2017 Yes $447,600 AWP
ciloleucel (Yescarta) cell lymphoma after
two or more lines of
systemic therapy,
including diffuse large
B‐ cell lymphoma
(DLBCL).

Treatment of adult

patients with
European Ex vivo, single
Human Gene Therapy
Axicabtagene relapsed or 8/23/2018 Yes N/A

Union dose
ciloleucel (Yescarta) refractory diffuse
large B‐cell
lymphoma (DLBCL).
Treatment of
primary mediastinal
Human Gene Therapy

Page 39 of 47
therapy.
large B‐cell
lines of systemic
after two or more
lymphoma (PMBCL),
39
Page 40 of 47

40
Adjunctive treatment in
European Ex vivo, $844,383(Italy);

haploidentical hematopoietic stem
Nalotimagene carmaleucel 8/18/2016 Yes $928,821 50,51
cell transplantation (HSCT) of adult Union multiple
(Zalmoxis) (Germany)
patients with high‐risk dose
hematological malignancies.
Recombinant adenovirus Wild‐type p53 gene (Ad‐p53) for In vivo,

encoding p53 (Gendicine) the treatment of head and neck China multiple 2003 NA $30,000 52
cancer. doses
Recombinant human E1B‐defective Ad for the treatment In vivo,

adenovirus type 5 H101 of head and neck cancer. China multiple 2005 NA $30,000 52
(Oncorine) doses
Retroviral expression In vivo,
Human Gene Therapy
vectors bearing Chemo therapy‐resistant metastatic Philippines multiple 2007 NA $35,000 53
inhibitory genes (Rexin‐ Solid tumor. doses

G)
Page 41 of 47

41
Local treatment of unresectable
Talimogene laherparepvec cutaneous, subcutaneous, and US In vivo, 10/27/2015 Yes $559,293 AWP

(Imlygic) nodal lesions in patients with multiple
melanoma recurrent after initial doses
surgery.
Treatment of adults with
unresectable melanoma that is European In vivo, $316,245
Talimogene laherparepvec 12/16/2015 No 54
regionally or distantly metastatic Union multiple (Germany)
(Imlygic)
(Stage IIIB, IIIC and IVM1a) with no doses
bone, brain, lung or other visceral
disease.
Human Gene Therapy
Monotherapy for the treatment
of melanoma in patients with In vivo, $237,677 public,
Talimogene laherparepvec Australia 11/16/2018 No 55
unresectable cutaneous, multiple $241,578 Private
(Imlygic)
subcutaneous or nodal lesions doses
after initial surgery.
Page 42 of 47

42
Treatment of patients up to 25 years
of age with B‐ cell precursor acute
lymphoblastic leukemia (ALL) that is
refractory or in second or later
Tisagenlecleucel relapse. US Ex vivo, 8/30/2017 Yes $570,000 AWP

(Kymriah) Treatment of adult patients with single
relapsed or refractory (r/r) large B‐cell dose
lymphoma after two or more lines of
systemic therapy including diffuse
large B‐cell lymphoma (DLBCL) not
otherwise specified, high grade B‐cell
lymphoma and DLBCL arising from
Human Gene Therapy
follicular lymphoma.
Page 43 of 47

43
Treatment of Pediatric and young
adult patients up to 25 years of age
with B‐cell acute lymphoblastic $
Tisagenlecleucel leukaemia (ALL) that is refractory, in European Ex vivo, 8/27/2018 Yes 416,481 56,57
(Kymriah) relapse Union single Germany;
post‐transplant or in second or dose $364,948
later relapse. Treatment of Adult UK
patients with relapsed or
refractory diffuse large B‐cell
lymphoma (DLBCL) after two or
more lines of systemic therapy.
Treatment of patients up to 25 years
Human Gene Therapy
of age with B‐ cell precursor acute
lymphoblastic leukemia (ALL) that is
refractory or in second or later
Tisagenlecleucel relapse. Canada Ex vivo, 9/5/2018 NA N/A
(Kymriah) Treatment of adult patients with single
Page 44 of 47

44
relapsed or refractory (r/r) large B‐cell dose
lymphoma after two or more lines of
systemic therapy including diffuse
large B‐cell lymphoma (DLBCL) not
otherwise specified, high grade B‐cell
lymphoma and DLBCL arising from
follicular lymphoma.
Treatment of: • Paediatric and young
with B‐cell acute lymphoblastic Ex vivo,
Tisagenlecleucel leukemia (ALL) that is refractory, in Switzerland 10/18/2018 No $371,000 58
single
(Kymriah) relapse post‐ transplant or in second dose
or later relapse. • Adult patients with
relapsed or refractory diffuse large B‐
Human Gene Therapy
cell lymphoma (DLBCL) after two or
more lines of
systemic therapy.

Page 45 of 47

45
Treatment of paediatric and young
with B‐cell precursor acute
lymphoblastic leukaemia (ALL) that is
Tisagenlecleucel (Kymriah) refractory, in relapse post‐transplant, Australia Ex vivo, 12/19/2018 No N/A

or in second or later relapse. single
Treatment of adult patients with dose
relapsed or refractory diffuse large B‐
cell lymphoma (DLBCL) after two or
more lines of systemic therapy.
Kymriah is not indicated for patients
with primary central nervous system
Human Gene Therapy
lymphoma.
Treatment of moderate knee
osteoarthritis (Kellgren & Lawrence Ex vivo,
Tonogenchoncel‐L (Invossa South Korea 7/12/2017 NA $5,501 59
grade 3) with symptoms (e.g. pain) single
Page 46 of 47

46
K) that persist despite three or more dose
months of conservative treatment
(medication, physical therapy, etc.)
Vascular endothelial Treatment of peripheral arterial In vivo,

Russia 12/7/2011 NA $6,600 60
growth factor gene disease (PAD) and its complication multiple
therapy (Neovasculgen) critical limb ischemia (CLI). doses
Vascular endothelial Treatment of peripheral arterial In vivo,

Ukraine 6/1/2013 NA N/A
growth factor gene disease (PAD) and its complication multiple
therapy (Neovasculgen) critical limb ischemia (CLI). doses
Treatment of patients with confirmed In vivo,
Voretigene neparvovec US 12/19/2017 Yes $1,020,000 AWP
Human Gene Therapy
biallelic RPE65 mutation‐associated single
(Luxturna)
retinal dystrophy. dose
Treatment of patients with confirmed In vivo,
Voretigene neparvovec Switzerland 7/13/2018 No N/A
biallelic RPE65 mutation‐associated multiple
(Luxturna)
Human Gene Therapy

Page 47 of 47
(Luxturna)
Voretigene neparvovec
retinal dystrophy.
retinal dystrophy.
biallelic RPE65 mutation‐associated
Treatment of patients with confirmed
Union
European
dose
doses
single
In vivo,
11/23/2018 Yes
N/A
47

Gene Therapy

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Human Gene Therapy

(Product name) Jurisdiction Market

Allogeneic pooled Critical limb ischemia due to India May 2016 NA $2,150 34

Remestemcel‐l Management of acute Graft Canada 5/17/2012 NA $200,000 36

Remestemcel‐l Rescue of patients NLT 6 New Zealandǂ 6/14/2012 NA N/A

Remestemcel‐l (Temcell) Acute Graft versus Host Disease Japan 9/18/2015 Yes $7,248 37

Thermosensitive Deep 2nd degree burns (skin South Korea 10/16/2015 NA N/A

Autologous adipose‐ Depressed scar South Korea 9/14/2007 Yes N/A

Autologous adipose‐ Crohn's disease South Korea 1/18/2012 Yes N/A

Autologous adipose‐ Remediation of hypodermic fat South Korea 3/26/2010 Yes N/A

Autologous bone Acute myocardial infarction South 7/1/2011 NA N/A

Autologous Metastatic renal cell carcinoma South 5/15/2007 NA N/A

Autologous Hepatoma South 8/6/2007 NA N/A

Autologous dendritic cells non‐small cell lung cancer South 2/14/2007 NA N/A

Autologous matural Malignant Lymphoma South 8/7/2007 NA N/A

Autologous Remediation of hypodermic fat defective location South 2/1/2010 NA N/A

Local bone formation‐‐local osteoblastic palpation South 8/26/2007 No N/A

Autologous Repair of symptomatic, full ‐thickness cartilage European

defects of the knee (grade III and IV of the Modified 6/27/2013 No $21,000 43

Autologous Repair of single or multiple symptomatic, full‐ US 12/13/2016 No $28,650 AWP

Autologous corneal Treatment of adult patients with moderate to European

Treatment of burn wounds South 5/3/2006 No N/A

keratinocyte cells Japan 9/29/2016 No N/A

fibroblasts (Cureskin) Remediation of depressed fibrotic scars location with South 5/11/2010 No N/A

acellular mucosal defects, soft China 2006 N/A N/A 39

Spheroids of human Repair of symptomatic articular cartilage defects of the European $9,000‐

associated (International Cartilage Repair Society [ICRS] grade III

Orphan Entry (US Source

Alipogene tiparvovec familial lipoprotein Unionǂ dose 10/25/2012 Yes (Germany) 48

Axicabtagene relapsed or 8/23/2018 Yes N/A

European Ex vivo, $844,383(Italy);

Recombinant adenovirus Wild‐type p53 gene (Ad‐p53) for In vivo,

Recombinant human E1B‐defective Ad for the treatment In vivo,

vectors bearing Chemo therapy‐resistant metastatic Philippines multiple 2007 NA $35,000 53

inhibitory genes (Rexin‐ Solid tumor. doses

Talimogene laherparepvec cutaneous, subcutaneous, and US In vivo, 10/27/2015 Yes $559,293 AWP

Tisagenlecleucel relapse. US Ex vivo, 8/30/2017 Yes $570,000 AWP

post‐transplant or in second or dose $364,948

Tisagenlecleucel (Kymriah) refractory, in relapse post‐transplant, Australia Ex vivo, 12/19/2018 No N/A

Vascular endothelial Treatment of peripheral arterial In vivo,

therapy (Neovasculgen) critical limb ischemia (CLI). doses

Vascular endothelial Treatment of peripheral arterial In vivo,

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